1. Technical Field
This invention generally relates to diagnostic imaging and novel contrast agent preparations and their use in diagnostic imaging, and more particularly relates to targeted contrast agents and methods for targeting contrast agents to cells and tissues for selective accumulation and retention in magnetic resonance imaging, for example, in visualizing tissue.
2. Prior Art
Imaging technology, including magnetic resonance imaging (MRI), has a vital role in the detection and treatment of cancer lesions and other illnesses. For example, MRI technology provides a powerful, non-invasive tool to map and explore the structure and function of soft tissues. In fact, MRI through the use of high-strength magnets and radio-frequency signals can produce three-dimensional images of tissues. With the improvements in the mechanical imaging system, it is possible to detect neoplastic lesions. However, the detection of early tumor lesions and metastases still remain challenging.
MRI contrast agents have been used to improve the intrinsic contrast of the images from imaging technology. This method relies on the administration of contrast agents to amplify the contrast in imaging between the pathological tissue and the normal tissue. The most widely used class of MRI contrast agents such as diethylenetriaminepentaacetate (DTPA) are based on gadolinium ion (Gd3+), manganese ion (Mn2+), and iron ion (Fe3+) chelates that are strictly extracellular low molecular weight compounds with T1 reflexivity. Ultimately, the efficacy of a contrast agent depends on both the inherent capability to improve images and the pharmacokinetics.
For example, the Gd3+ based contrast agents approved for clinical use are mainly non-specific small molecules. Such Gd3+ contrast agents usually have relaxivities of <10 mM−1s−1 which are 20 to 50 fold lower than the predicted values. The relaxivities are mainly limited by the rotational correlation time of the molecule. The most commonly used contrast agent, DTPA, has a R1 relaxivity of 5 mM−1s−1. With this relaxivity, a robust clinical examination usually requires a large dose (>0.1 mM local concentration) in order to reach sufficient contrast or to produce an acceptable image. In addition, this class of contrast agents has a very short circulation time that limits the time window for data collection. Efforts to improve such contrast agents have included the covalent or the non-covalent linkage of the small Gd3+ agent to the macromolecules, such as dendrimers or copolymers.
Although considerable progress has been made in the field of contrast agents, contrast agents that can be targeted effectively to specific cells and tissues are still lacking. While the delivery of contrast agents is one of the more important issues, there has been a lack of development of MRI contrast agents able to target specific molecular markers. While many tissue specific contrast agents demonstrate favorable relaxation properties, such contrast agents tend not be designed to recognize specific cellular markers.
Accordingly, there is always a need for improved contrast agents that may be targeted to specific tissues. There also is a need for protein-based contrast agents, capable of being targeted, with wide applicability in molecular imaging of various tissues, tumors, cancers, and diseases. There also is a need for safer contrast agents. It is to these needs among others that this invention is directed.